N-methyl-D-aspartate (NMDARs) play critical roles in information processing and in the synaptic plasticity that underlies learning and memory. Depending upon their pattern of activation, NMDARs can promote long- term potentiation (LTP) or long-term synaptic depression (LTD), two leading candidates for memory mechanisms in the mammalian brain. When activated excessively, NMDARs also cause several forms of neurodegeneration. Importantly, it appears that different subclasses of NMDARs and different signaling pathways contribute to synaptic plasticity and neurodegeneration. We have observed that there are also conditions, intermediate between synaptic plasticity and neurodegeneration, in which NMDAR activation produces no change in synaptic responses or neuronal injury but inhibits the ability to generate LTP. This NMDAR-mediated LTP inhibition is observed with low level activation of NMDARs, certain patterns of synaptic stimulation and exposure to sub-lethal stressful conditions (brief hypoxia, low glucose and ammonia). Because of the role that synaptic plasticity appears to play in memory processing, this NMDAR- mediated LTP inhibition may be important for understanding cognitive defects that accompany untimely NMDAR activation in neuropsychiatric disorders. In this proposal, we will extend our initial work on NMDAR LTP inhibition by examining factors that contribute to this form of synaptic modulation. The aims of our studies are 1. To determine the role of subclasses of NMDARs in LTP inhibition;2. To determine intracellular pathways contributing to NMDAR-mediated LTP inhibition with emphasis on evidence indicating that specific molecular subclasses of NMDARs couple to different classes of intracellular messengers;and 3. To determine whether NMDAR-LTP inhibition represents a form of metabolic stress with emphasis on pursuing preliminary studies indicating that alternative energy substrates such as pyruvate overcome the LTP inhibition when administered following untimely NMDAR activation. These studies will be conducted in the CA1 region of rat hippocampal slices, an area known to be important for memory processing. The long-term goal of our studies is to identify ways to preserve and restore synaptic function in individuals with neuropsychiatric disorders.